PROJECT SUMMARY Obesity is a major public health problem that affects approximately 35% of US adults and results in over $147 billion in annual health care expenditures. Obesity is associated with several age-related diseases (type 2 diabetes, cardiovascular disease, cancer, cognitive impairment/Alzheimer's) and the most recent data from the CDC indicates that middle-aged men and women and older women are more susceptible to obesity compared to their younger counterparts. Increased prevalence of obesity in older adults is particularly alarming since this population's census is expected to double by 2050. Because of the increasing prevalence of obesity and its association with age-related diseases, identifying novel interventions that can reduce adiposity is essential to decrease the burden of obesity on our health care system and improve the healthspan of older Americans. Recently, our lab has shown that manganese tetrakis benzoic acid porphyrin (MnTBAP), a super oxide dismutase (SOD) mimetic, reduces diet-induced obesity, insulin resistance, and inflammation. Because aging and obesity are tightly coupled to increases in oxidative stress and inflammation, MnTBAP may reduce age- related obesity and associated diseases. Our preliminary data shows that MnTBAP may inhibit the pro- inflammatory protease activated receptor 2 (PAR2) signaling pathway and activate the adenosine monophosphate activated protein kinase (AMPK). PAR2 is a G protein coupled receptor that promotes inflammation and has recently been shown to play a role in the development of obesity and insulin resistance. Specifically, we demonstrate that MnTBAP treatment reduces the expression of PAR2 and tissue factor (TF), an activator of PAR2 signaling, as well as increase the expression of cathepsin G (CTSG) and proteinase 3 (PRTN3), two endogenous inhibitors of PAR2 signaling. AMPK is a master regulatory of cellular energy homeostasis and has recently been shown to be inhibited by PAR2 signaling. Therefore, our first aim is to determine if MnTBAP treatment can prevent or attenuate age-related obesity and improve healthspan (insulin sensitivity, vascular function, blood pressure, inflammation, blood lipids). Our preliminary data also suggests that MnTBAP increases AMPK activity and we suspect this may be related to an inhibition of TF-PAR2 signaling. Therefore, our second aim is to demonstrate that MnTBAP treatment antagonizes the TF-PAR2 signaling pathway, a process that increases AMPK activity by decreasing AMPK's interaction with ?-arrestin 2. Finally, our third aim of this proposal is to demonstrate that intact PAR2 signaling is required for the development of age-related obesity, insulin resistance, and inflammation. Results from this proposal will provide evidence supporting the use of SOD mimetics and PAR2 inhibitors as potential treatments for age- related obesity, insulin resistance, and inflammation.